Ketamine and depression - M. Korostyński

MOLECULAR MARKERS OF ANTIDEPRESSIVE EFFECTS OF KETAMINE

In clinical trials, the NMDA receptor
antagonist ketamine was found to act as an antidepressant with rapid and
persisting effects, even in otherwise treatment-refractory cases.
Identification of the mechanisms underlying ketamine’s antidepressant action
may enable the development of novel drugs, with similar clinical properties but
lacking undesirable psychotomimetic effects.

This instrument
was used to analyze drug-effects of gene expression in the mouse brain.
Measurement of RNAs abundance levels was done at the level of the whole-transcriptome.

Screening for genes involved in the effects of NMDA
antagonists has been performed at several time points (1, 2, 4 and 8 h)
following acute administration of ketamine, memantine, and phencyclidine in
mice. Gene expression alterations were analyzed in striatum and hippocampus by
applying whole-genome microarray profiling. We identified 52 transcripts with
altered expression in response to treatment with NMDA receptor antagonists.
Functional analysis indicated links that connect expression of the regulated
genes to the intracellular signaling pathways related to MAPK, IL-6, and
metabolism of insulin. Moreover, to obtain a more detailed molecular profile of
ketamine, its transcriptional effects were further analyzed using
next-generation sequencing. Consequently, ketamine-regulated expression of
specific gene isoforms was detected. On top of that, gene expression
alterations induced by the selected NMDA antagonists were compared to the
molecular profiles of psychotropic drugs: antidepressants, antipsychotics,
anxiolytics, psychostimulants and opioids.

Figure 2.
Molecular classification of ketamine in a comparison to several psychotropic
drugs with diverse mechanisms of pharmacological action.

The profile of gene
expression alterations induced by ketamine was compared to the effects of
antidepressants, antipsychotics, anxiolytics, psychostimulants, and opioids.
Bioinformatics analyses were done by using hierarchical clusterization (diagram
on the left side), PCA (middle) and heatmap (right side).

The comparison with other psychotropic drugs revealed
that the molecular effects of ketamine are most similar to memantine, and
phencyclidine. Based on the expression profile, the NMDA antagonist was placed
among fluoxetine, tianeptine, as well as opioids and ethanol. The identified
patterns of gene expression alterations in the brain provided novel molecular
classification of ketamine. The transcriptional profile of ketamine reflects
its multi-target pharmacological nature and reveals similarities between the
effects of ketamine and monoaminergic antidepressants. This effect together
with NMDA receptors blockade may explain the mechanisms of ketamine’s rapid
antidepressant action observed in clinics.